KR20080109088A - Rosuvastatin zinc salt - Google Patents

Abstract

The present invention relates to a rosuvastatin zinc salt of formula (I), a process for its preparation and a medicament containing such salt:

The rosuvastatin zinc salt according to the present invention is prepared by reacting rosuvastatin with zinc alcoholate, zinc enolate or inorganic or organic zinc salt and isolating the rosuvastatin zinc salt (2: 1) thus obtained.

Description

Rosuvastatin Zinc Salt {ROSUVASTATIN ZINC SALT}

The present invention provides (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methyl-sulfonylamino) pyrimidine-5 of formula (I) -Yl]-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid, hydrates thereof, methods for preparing the same, pharmaceuticals containing such salts, methods for preparing pharmaceuticals and the use of such salts in medicine will be:

(+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methyl-sulfonyl-amino) -pyrimidine-5- of formula (II) Il]-(3R, 5S) -dihydroxy- (E) -6-heptene-carboxylic acid is known by the international generic name (INN) rosuvastatin:

Rosuvastatin of formula (II) was first introduced in European Patent 521471. The calcium salt of rosuvastatin is used in medicine for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

The Agency applies strict quality standards for pharmaceutical active ingredients. Some of these criteria relate to the chemical purity and stability of the pharmaceutically active ingredient. Another pharmacologic requirement is that the manufacture of a satisfactory quality drug and that the drug must have adequate stability. These criteria are determined and disclosed by the corresponding pharmacopoeia provisions.

In the case of rosuvastatin of formula (II), the basic requirements of the active pharmaceutical ingredient for use in medicine are high purity, suitable stability and the possibility of simple formulations.

According to published international patent application WO 00/042024, the amorphous rosuvastatin of formula (II) obtained according to the process of European patent 521471 can have a number of difficulties when used in pharmaceutical techniques. To overcome this drawback, crystalline forms are produced with more beneficial physical properties than amorphous products. However, the preparation of crystalline rosuvastatin calcium salt is a manufacturing process that requires a high production volume and results in a large loss of material.

The basic problem in the preparation of rosuvastatin calcium salt is that the primary product obtained is poorly filterable and cannot be purified in an easy manner. Published international patent application WO 04/14872 describes amorphous products with advantageous filterability. According to the process of this application, a calcium salt of advantageous particle size is prepared by reacting an alkali metal, ammonium, methylammonium or tris (hydroxymethyl) -methylammonium salt of rosuvastatin with calcium chloride in an aqueous solution.

Published international patent application WO 01/60804 describes ammonium-, lithium- or magnesium salts of rosuvastatin of formula (II) of high purity in order to solve the production problems that occur during the preparation of amorphous rosuvastatin. Starting from the salts mentioned above, it is possible to prepare amorphous rosuvastatin of a quality suitable for the manufacture of a medicament.

A similar process is described in published international patent application WO 2005/051921, in which the isopropylammonium or cyclohexylammonium salt of rosuvastatin is produced in high purity, which salt is the sodium salt or high purity amorphous calcium salt of rosuvastatin. Is converted to.

Published international patent application WO 2005/040132 describes amorphous rosuvastatin calcium salts of high diastereomeric purity. According to the described process, the primary product amorphous rosuvastatin calcium salt is crystallized in the first step and the product thus obtained is subsequently converted to amorphous.

In summary, according to the art, it can be concluded that the preparation of rosuvastatin calcium salt suitable for the manufacture of pharmaceuticals is a particularly complex process. The crude product must undergo further purification and crystallization steps to obtain a product that is suitable for purity and physical properties. It is difficult to carry out industrial scale processes with known processes, which are often uneconomical, resulting in significant loss of material.

Summary of the Invention

The purpose of our investigation-development work is to maintain or enhance the pharmacological effects characteristic of the statin group, and [(+)-7 of formula (II) having high stability, which can be produced at a quality suitable for pharmaceutical preparation. -[4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -dihydroxy- It is to develop a novel salt of (E) -6-heptenecarboxylic acid.

This object is solved according to the present invention.

The present invention relates to (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methyl-sulfonylamino) pyrimidine-5- of formula (I). The zinc salt of the general]-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid and its ringed form meets all of the above criteria, and since the salt is suitable for drug production, And the surprising finding that it has excellent stability to light and can be produced in high purity by an industrially convenient process.

In a first aspect of the invention there is provided a rosuvastatin zinc salt of formula (I), which can be prepared directly in high purity suitable for the manufacture of a medicament. The rosuvastatin zinc salt of formula (I) is novel.

The advantage of the rosuvastatin zinc salt of formula (I) as compared to the calcium salt of rosuvastatin known according to the art is that it is produced in high quality by a simple process in which the zinc salt can be easily scaled up for industrial production. It can be. An additional advantage of rosuvastatin zinc salt is that it can be manipulated very easily and no further processing is required due to the pretreatment of the primary product for pharmaceutical formulation.

The rosuvastatin zinc salt of formula (I) is stable to heat and light, which is advantageous during pharmaceutical processing, during formulation and during use as a medicament. The product can advantageously be used for the treatment of disorders of lipid metabolism such as hypercholesterolemia, cyclopoproteinemia and atherosclerosis.

In a second aspect of the present invention there is provided a process for preparing the rosuvastatin zinc salt of formula (I), comprising reacting rosuvastatin of formula (II) with a zinc compound.

In a first modified process suitable for the preparation of rosuvastatin zinc salt of formula (I), (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- of formula (II) (N-methyl-N-methyl-sulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid reacts with zinc alcoholate, thus The rosuvastatin zinc of formula (I) obtained is isolated.

As zinc alcoholate, compounds of formula (III) can be used in 0.5 to 0.6 molar equivalents based on the molar amount of rosuvastatin of formula (II):

R-O-Zn-O-R III

Wherein R represents a straight or branched chain alkyl group having 1 to 4 carbon atoms.

The reaction is carried out in a solvent. Suitable solvents include aliphatic alcohols having 1 to 4 carbon atoms such as methanol, ethanol, 2-propanol or 1-butanol; Aliphatic ketones having 3 to 8 carbon atoms; Aliphatic esters having 2 to 8 carbon atoms or aliphatic ethers having 4 to 8 carbon atoms or mixtures thereof.

The preparation of the salt is carried out at room temperature and at the boiling point of the solvent, preferably at a temperature of 25 to 50 ° C.

The product is separated by evaporation of the solvent. Optionally, the solution can be treated with silica gel before solvent evaporation. The evaporation residue is triturated with excess ether of 4 to 8 carbon atoms, preferably diethyl ether, and the solid thus obtained is filtered off.

A second possible product separation method is to dissolve the evaporated residue obtained without silica treatment in aliphatic esters having 2 to 8 carbon atoms and to treat the solution thus obtained with silica. After repeated filtration, the solvent is partially evaporated and the residue is stirred with an excess of ether having 4 to 8 carbon atoms, preferably diethyl ether, and the precipitated product is filtered off.

In a second modified process, rosuvastatin of formula (II) is reacted with zinc enoleate of formula (IV):

Zinc enoleate of formula (IV) is used in 0.5 to 0.6 molar equivalents based on the molar amount of rosuvastatin of formula (II).

The reaction of the compounds of the formulas (II) and (IV) is carried out in a solvent. Suitable solvents are aliphatic alcohols having 1 to 4 carbon atoms. The reaction can be carried out at room temperature and at the boiling point of the solvent, preferably 25-40 ° C.

The product can be separated by treating the solution with silica, filtration, evaporating the solvent to concentrate the solution and precipitating the product by adding an excess of ether having 4 to 8 carbon atoms, preferably diethyl ether. .

In a third modified process for preparing the rosuvastatin zinc salt of formula (I), (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2 of formula (II) Inorganic or organic alkali metal salts of-(N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid React with the zinc salt and the product of formula (I) thus obtained is separated.

In this process, zinc salts of inorganic or organic acids can be used. Preferred zinc salts are zinc chloride, zinc sulfate or zinc acetate.

The starting material is preferably the sodium salt of the compound of formula (II).

The reaction can be carried out in water using a water soluble zinc salt such as zinc chloride, zinc sulfate or zinc acetate. The reaction can be carried out in an organic solvent such as aliphatic alcohol having 1 to 4 carbon atoms; It may be carried out in ketones or aliphatic nitriles having 3 to 10 carbon atoms including acetone such as acetonitrile. The above-mentioned solvents can be used in the form of a mixture mixed with each other or with water.

In a preferred embodiment of the process, zinc chloride dissolved in ethanol or water or zinc sulfate dissolved in water is used and the reaction is carried out at a temperature of 25 to 50 ° C.

In a particularly preferred embodiment of the invention, the sodium salt of rosuvastatin of formula (II) is reacted with 0.5 molar equivalents of zinc sulfate in an aqueous solution at a temperature of 25 to 40 ° C. The product is separated as an aqueous reaction mixture by filtration or by washing the product from an aqueous solution using an insoluble solvent. The organic phase is then separated, concentrated to a small volume, and the rosuvastatin zinc salt of formula (I) is separated.

Advantageous insoluble solvents for the extraction of rosuvastatin zinc salts of formula (I) are aliphatic esters having 2 to 8 carbon atoms, which are good solvents for rosuvastatin zinc salts, for example ethylformate, ethylacetate or methylacetate. to be. The rosuvastatin zinc salt of formula (I) is isolated by concentrating the extract in small volumes and precipitating the rosuvastatin zinc salt by adding ethers having 4 to 8 carbon atoms, preferably diethyl ether.

The rosuvastatin zinc salt according to the invention is similar to other rosuvastatin salts, for example calcium salts, known according to the art, none of which have a clear melting point. Thus, the rosuvastatin zinc salt according to the invention is characterized by the melting start temperature in the examples.

In addition, the zinc salt of rosuvastatin according to the invention can be obtained in anhydrous and hydrated forms. Rosuvastatin zinc salts of formula (I) are generally obtained in hydrate form when a solvent is used during their preparation in an aqueous solvent or solvent mixture. In this case, however, when an organic solvent is used during the salt formation reaction, an anhydrous form is produced.

 In a further aspect of the invention there is provided a pharmaceutical product comprising a rosuvastatin zinc salt of formula (I) mixed with one or more pharmaceutically acceptable vehicles or adjuvants.

The pharmaceutical product according to the invention generally contains from 0.1 to 95% by weight, preferably from 1 to 50% by weight and most preferably from 5 to 30% by weight of the active pharmaceutical ingredient.

The pharmaceutical product according to the invention may be orally (eg in the form of powders, tablets, coated tablets, chewing tablets, capsules, microcapsules, granules, dragees, lozenges, solutions, suspensions or emulsions), parenteral (eg , In the form of intravenous, intramuscular or intraperitoneal injections or infusions), rectal (suppositories or retention enemas), intradermal (eg patches), implantation, or topical (eg ointments, creams or In the form of a patch). Solid, semisolid or liquid pharmaceutical preparations containing the rosuvastatin zinc salt of formula (I) may be prepared according to pharmaceutical techniques known in the art.

Solid pharmaceutical products containing rosuvastatin zinc salts of formula (I) prepared for oral administration include vehicles or fillers (e.g. lactose, glucose, starch, calcium phosphate, microcrystalline cellulose), binders (e.g. For example, gelatin, sorbitol, polyvinylpyrrolidone), disintegrants (e.g. croscarmellose, sodium carboxymethylcellulose, crospovidone), tableting aids (e.g. magnesium stearate, talc, polyethylene glycol, Silicic acid, silica, silicon dioxide) and surfactants (eg, sodium laurylsulfate).

Liquid pharmaceutical products containing the rosuvastatin zinc salt of formula (I) suitable for oral administration may be prepared in the form of solutions, syrups, suspensions or emulsions, and may be prepared as suspending agents (e.g., gelatin, carboxymethylcellulose), Emulsifiers (sorbitan monooleate), solvents (eg water, oil, glycerol, propylene glycol, ethanol), buffers (eg acetate, phosphate, citrate buffer) or stabilizers (eg Methyl-4-hydroxy-benzoate).

Liquid pharmaceutical products containing rosuvastatin zinc salts of formula (I) prepared for parenteral use are sterile isotonic solutions which may contain preservatives and buffers in addition to solvents.

Semi-solid pharmaceutical products containing rosuvastatin zinc salts of formula (I) For example suppositories contain the active ingredient uniformly dispersed in the vehicle of the preparation (eg polyethylene glycol or cocoa butter).

A pharmaceutical product containing the rosuvastatin zinc salt according to the invention as the active ingredient contains the compound in unit dosage form.

A further aspect of the present invention is the use of rosuvastatin zinc salt of formula (I) for the manufacture of a medicament.

Pharmaceutical products containing rosuvastatin zinc salts according to the invention can be produced using pharmaceutical techniques known in the art. The active ingredient is mixed with a pharmaceutically acceptable vehicle or adjuvant in solid or liquid, and the mixture is directed to the pharmaceutical dosage form. Such methods and pharmaceutically acceptable vehicles or adjuvants are known in the literature (Remington's Pharmaceutical Sciences, Edition 19, Mack Publishing Co., Easton, USA, 1990).

A further aspect of the invention is a method of treating hyperlipoproteinosis, hypercholesterolemia and atherosclerosis, comprising administering a clinically effective amount of a rosuvastatin zinc salt according to the invention to a patient in need of such treatment. Way.

Further details of the invention are set forth in the following examples, and the scope of the invention is not limited by these examples.

Example 1

(+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

4.16 mmol (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R , 5S) -dihydroxy- (E) -6-heptenecarboxylic acid was dissolved in 70 ml methanol and 0.60 g (2.13 mmol) zinc acetylacetonate monohydrate was added to this solution at room temperature. The reaction mixture was stirred for 8 hours at room temperature. After this period, 1.0 g of silica was added and the reaction mixture was stirred for 30 minutes. The mixture was filtered and the solvent was evaporated to concentrate the filtrate to 1/10 volume. The residue was mixed with 20 volumes of diethyl ether and the precipitate was filtered off, washed with diethyl ether and dried at 40 ° C. under vacuum. This gave 2.05 g (93%) of product, which began to melt at a temperature of 137 ° C.

Example 2

(+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

3.85 g (8.0 mmol) of (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl ]-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid is dissolved in 40 ml of ethyl acetate and in this solution a solution of 0.62 g (4.0 mmol) zinc ethylate in 40 ml of ethanol. Added. The reaction mixture was refluxed for 2 hours. The reaction mixture was cooled down, filtered and the solvent evaporated. The residue was triturated with 50 ml diethyl ether. The suspension is filtered, the solid is dissolved in 50 ml ethyl acetate and the solution is stirred with 2 g of silica gel for 3 hours. The silica gel was filtered off, 2/3 volume of solvent was evaporated and the residue was stirred with 10 times volume of diethyl ether. The precipitated salt was filtered off, washed with diethyl ether and dried. This gave 2.8 g (68%) of rosuvastatin zinc salt, which began to melt at 137 ° C.

Example 3

(+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

The procedure described in Example 2 is followed except that the reaction is carried out by stirring the reaction mixture for 16 hours at room temperature. This gave 3.0 g (73%) of rosuvastatin zinc salt.

Example 4

(+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

4.16 mmol (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R , 5S) -dihydroxy- (E) -6-heptenecarboxylic acid was dissolved in 70 ml of ethyl acetate, and 4.2 ml (1.0 mmol / ml) of ethanol sodium ethylate solution prepared directly in this solution was prepared at room temperature. Under addition. While stirring, 2.0 mmol zinc chloride solution prepared in 10 ml of ethanol was added over 30 minutes. The reaction mixture was stirred at 50 ° C. for 2 hours, cooled to room temperature and filtered. The filtrate was evaporated to 1/10 volume and the product precipitated with 10 times volume of diethyl ether. The product was then filtered and dried at 50 ° C. 1.8 g (86%) of rosuvastatin zinc salt was obtained, which began to melt at 136 ° C.

Example 5

(+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

The title compound was prepared according to the process of Example 4 except that the reaction was carried out at room temperature. This gave 1.65 g (77%) of the title compound, which began to melt at 137 ° C.

Example 6

(+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -Dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1)

To prepare the title compound according to the process of Example 4, except that 2.0 mmol zinc sulfate dissolved in water was used as a reagent, and the reaction was performed at room temperature. After separation of the aqueous layer, the product was separated by evaporation of 2/3 solvent and the residue was triturated with 10-fold volume of diethyl ether. The precipitated solid was filtered off and dried at a temperature of 50 ° C. This gave 1.76 g (81%) of rosuvastatin zinc salt, which began to melt at 138 ° C.

Claims (18)

(+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl of the formula (I) -(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1) or a hydrate thereof: (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl of the formula (I) A process for preparing-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1), wherein (+)-of formula (II) 7- [4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -pyrimidin-5-yl]-(3R, 5S) -dihydrate A process comprising reacting a oxy- (E) -6-heptene-carboxylic acid or a salt thereof with an inorganic or organic zinc compound and isolating the rosuvastatin zinc salt of formula (I) thus obtained: 3. The (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -pyri of claim 2 Midin-5-yl]-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid, wherein the alcoholate moiety contains an alkyl group having from 1 to 4 carbon atoms After reacting with zinc alcoholate of, the method is characterized in that the rosuvastatin zinc salt of formula (I) is separated: R-O-Zn-O-R III A compound according to claim 2, wherein (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidine of formula (I) For the preparation of -5-yl]-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1), rosuvastatin of formula (II) is prepared as Zinc enolate of IV) preferably reacted with zinc acetylacetonate and separating the rosuvastatin zinc salt of formula (I) thus obtained: The compound of claim 2, wherein (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] Alkali metal of — (3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid Preferably, the salt with sodium is an inorganic or organic zinc salt, preferably zinc chloride, zinc sulfate or acetic acid. Reacting with zinc and separating the rosuvastatin zinc salt of formula (I). The process according to claim 2, wherein the salt formation is carried out at a boiling point of room temperature to the solvent, preferably at a temperature of room temperature to 50 ° C. 7. The salt formation according to any one of claims 2 to 5, wherein the salt formation is water, aliphatic alcohols having 1 to 4 carbon atoms, aliphatic ketones having 3 to 8 carbon atoms, aliphatic esters having 3 to 8 carbon atoms, carbon A process selected from aliphatic nitriles having 2 to 5 atoms or aliphatic ethers having 4 to 8 carbon atoms, preferably ethanol, acetone, acetonitrile, ethyl acetate or dioxane. The zinc alcoholate, zinc enoleate or inorganic or organic zinc salt used for salt formation is 0.5 based on the molar amount of rosuvastatin of formula (II) or a salt thereof. To 0.6 molar equivalent weight. The process according to any one of claims 2 to 5, characterized in that the rosuvastatin zinc salt of formula (I) is separated from the reaction mixture by precipitation or extraction. 10. The process according to claim 9, wherein the extraction is carried out using aliphatic esters having 2 to 8 carbon atoms. 10. The process according to claim 9, wherein precipitation is carried out using an ether type antisolvent having 4 to 8 carbon atoms and an aliphatic ester type solvent having 2 to 8 carbon atoms optionally mixed with an aliphatic ether having 4 to 8 carbon atoms. Characterized in that it is performed. The crude rosuvastatin zinc salt of formula (I) is mixed with an extract with an aliphatic ether type solvent having 4 to 8 carbon atoms and the precipitated rosuvastatin zinc salt of formula (I) Separating from the extract by separating. The process according to claim 2, wherein the rosuvastatin zinc salt of formula (I) is obtained in amorphous, crystalline or partially crystalline form. (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-( Use of 3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1). (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl] of formula (I)- A pharmaceutical product containing (3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1) together with one or more pharmaceutically acceptable vehicles or adjuvants. A method of preparing a medicament according to claim 15 comprising mixing the rosuvastatin zinc salt according to claim 1 with a pharmaceutically acceptable vehicle or adjuvant and converting the mixture into a pharmaceutical dosage form. (+)-7- [4- (4-fluorophenyl) -6-isopropyl-2 of formula (I) for the manufacture of a medicament suitable for the prophylaxis or treatment of hypercholesterolemia, hyperlipoproteinemia or atherosclerosis Of (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1) Usage. A method of treating hypercholesterolemia, hyperlipoproteinemia or atherosclerosis, the method comprising treating a patient in need thereof with a pharmacologically effective amount of (+)-7- [4- (4-fluorophenyl)-according to claim 1 6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) pyrimidin-5-yl]-(3R, 5S) -dihydroxy- (E) -6-heptenecarboxylic acid zinc salt (2: 1).